Materials that enable the targeted delivery via controlled release of active materials can be valuable. Ideally, a delivery mechanism possesses high solubility for the active, robust containment abilities to avoid leakage during processing, storage and use, and is inexpensive and flexible for use with various active materials and delivery methods. Currently, vesicles or liposomes (dispersed lamellar liquid crystalline particles) can be used to contain and deliver active materials. However, liposomes are not long lasting, stable structures.
Liposome delivery alternatives include three forms of cubic liquid crystalline phase materials (precursor, bulk, and particulate (i.e. cubosomes)). Precursor materials are usually liquid and form a cubic phase in response to dilution. Bulk and particulate forms of cubic phase are viscous isotropic gel-like materials, often with an active ingredient, such as a drug, incorporated in its structure. Landh, U.S. Pat. No. 5,531,925 describes the production of powdered precursors by freeze-drying cubic phase particles containing proteins. However, the sticky nature of the monoglyceride and the high shear dispersion required to form cubic gel particles makes this type of powder difficult to work with as there is a tendency for clumping. Further, these types of powders are not necessarily colloidially stable upon hydration. Additionally, on a large scale, freeze-drying processes are significantly more expensive than spray-drying techniques. Finally, Landh does not discuss the encapsulation of a monoglyceride with encapsulants. It is believed that encapsulation can be necessary to form non-cohesive powders that form colloidally stable cubic liquid crystalline particles upon hydration.
Further, after complete hydration of the monoolein to form a bulk or particulate dispersion form of cubic phase, the cubic phase is then applied to a target environment, such as body tissue. The active can then diffuse out of the cubic phase in a controlled release fashion as a result of its complex internal bicontinuous structure. Cubic phase particles are typically produced by high-energy dispersion of bulk cubic gel, followed by colloidal stabilization through significant addition of polymer, up to 12% w/w according to Gustafsson et al., “Submicron particles of Reversed Lipid Phases in Water Stabilized by a Nonionic Amphiphilic Polymer,” Langmuir, 13, 6964–71 (1997), herein incorporated by reference. This type of process can require a significant amount of water and energy input thereby limiting the flexibility of a formulation using such particles.
Leser, WO 99/47,004, discloses a food ingredient in aqueous or instant powder form, containing a monoglyceride that forms a cubic, lamellar or hexagonal structure encapsulating or associating the food ingredient. Leser is primarily concerned with the encapsulation of food ingredients with liquid crystalline materials. However, Leser does not disclose the use of a hydrotrope additive in powder formation to avoid the formation of cubic liquid crystalline gel during drying. Additionally, Leser does not disclose powder precursors that form cubic liquid crystalline particles that are immediately colloidally stabilized upon hydration.
Yuan, WO 00/23,517, discloses a high-amylose starch-emulsifier (monoglyceride) composition forming a complex for food and beverage applications. This complex is used to incorporate fat into food formulations rather than create liquid crystalline particles. Powder, gel, and paste forms are disclosed for food property adjustment, not controlled-release or pharmaceutical applications. Yuan does not disclose the use of hydrotrope to avoid liquid crystalline formation during drying of powders.
Nickel, WO 96/03,056, describes inclusion complex production for use as delivery vehicles of fats and oils into food products as emulsions. Again, Nickel does not disclose controlled-release liquid crystalline particles or the use of hydrotropes.
Szoka, U.S. Pat. No. 5,811,406, discloses freeze-dried powders forming “lipoplexes” or lamellar liquid crystalline liposomes complexed with DNA and other biological proteins. The powders can be used to deliver the bioactive materials to the respiratory tract, where they hydrate to form lamellar liposomes that deliver the bioactives to the adjacent cells. While monoolein is specified as a surfactant for use in forming liposomes, it is only in combination with other surfactants and is not used to form cubic phase. Cubic liquid crystalline particles are more robust (against degradation) than and structurally distinct from liposomes.
Guerin, WO 97/15,386, discloses the formation of detergent granules containing liquid-phase active ingredients by spray-drying a water-in-oil emulsion that lacks a cubic phase. Hydration of these powders does not produce colloidally stable particles but instead forms a detergent solution. Additionally, Guerin does not disclose additional starting liquids like isotropic solutions and liquid crystalline materials, nor do they utilize encapsulating compounds.
Anderson, WO 99/12,640, discloses bicontinuous cubic liquid crystalline particles coated by solid crystalline materials (i.e., metals) as controlled delivery and uptake devices that either shed their coating to function or have a porous coating. These particles, however, are limited to having nanostructured liquid or liquid crystalline materials (such as a fully hydrated bicontinuous cubic phase) in their cores. Further, the use of encapsulants that dissolve and provide colloidal stabilizaion benefits or the use of hydrotropes to aid a spray-drying processes are not mentioned.
Finally, Yajima et al., WO 96/34,628, discloses a drug having an unpleasant taste, a polymer solution in the stomach, and monoglyceride crystals. There is no use of the unsaturated monoglyceride, monoolein, only the saturated monostearin. Additionally, bicontinuous cubic or cubic hybrid liquid crystalline structures are not disclosed.
As used herein, “Amphiphilic substance” means a molecule with both hydrophilic and hydrophobic (lipophilic) groups. Amphiphilic substances generally spontaneously self-associate in aqueous systems and form various aggregates. Exemplary, but non-limiting, aggregates include lamellar phases, hexagonal phases, and cubic phases. These phases are thermodynamically stable. The long-range order in these phases, in combination with liquid-like properties in the short-range order, gave rise to the notation “liquid crystalline phases”.
Cubic Gel Precursors
Smectic liquid crystalline phases (i.e., bulk cubic liquid crystalline gels and dispersions of cubic liquid crystalline gel particles) can be formed from precursors including an amphiphilic molecule such as a lipid and a polar liquid. The cubic liquid crystalline gel phase structures can form in response to some event, such as a temperature change or dilution of the precursor. In some applications, a cubic gel precursor forms a bulk cubic liquid crystalline gel only when needed for the specific application. For example, precursors have been used in antiperspirants, in which a water-insoluble liquid crystalline phase forms when the precursor contacts sweat (salt water). The resulting bulk liquid crystalline gel has a cubic or hexagonal liquid crystal structure that blocks pores. Precursors have also been used to deliver a therapeutic agent to treat periodontal disease, for example, by putting the precursor comprising a monoglyceride and an active ingredient into a reservoir such as a periodontal pocket. The precursor forms bulk cubic liquid crystalline gel on contact with saliva and then provides controlled release of the therapeutic agent.
However, in these applications, some uncontrolled stimulus (such as sweating or salivating) is required for the precursor to form a bulk cubic liquid crystalline gel. Further, the precursor is generally not a powder, but a liquid. Control of the bulk cubic liquid crystalline gel properties can be difficult. Furthermore, it can be difficult to form a particulate cubic liquid crystalline gel directly from the precursor. Therefore, there is a need to provide a substantially dehydrated precursor that can directly form either bulk or particulate cubic liquid crystalline gels. There is a further need to provide a method for using the precursor to prepare bulk and particulate cubic liquid crystalline gels with controlled properties.
Bulk Cubic Liquid Crystalline Gel
The liquid crystalline phases have distinct hydrophilic and hydrophobic domains, which give them the ability to dissolve (solubilize) or disperse water-soluble, oil-soluble, and amphiphilic compounds. Liquid crystalline phases are highly ordered structures that restrict the diffusion of added ingredients, thereby making them useful for controlled-release purposes. Cubic liquid crystalline phases can be prepared as pastes and thus are particularly useful as delivery vehicles due to their rheological properties. Cubic liquid crystalline phases are also advantageous in that they are mechanically robust and resistant to physical degradation.
Bulk cubic liquid crystalline gels prepared in advance (i.e., before administration rather than in situ) can also be used as controlled release reservoirs of pharmaceutical materials. However, bulk cubic liquid crystalline gels can be difficult to prepare due to the properties of the raw materials and Theological properties of the gels themselves. Lipids that yield cubic liquid crystalline phases, such as monoglycerides, are typically waxy solids at room temperature. Therefore, the bulk cubic liquid crystalline gel is prepared by equilibration, at high temperature or over many hours, or both, because transport of water can be slow through solid lipids. Processes requiring long hold times at high temperatures to manufacture bulk cubic liquid crystalline gels are not economically, or commercially, practical. Therefore, a further need exists to provide a commercially feasible method for forming a bulk cubic liquid crystalline gel at relatively low temperature (e.g., room temperature), and in a relatively short amount of time (e.g., within minutes).
Bulk cubic liquid crystalline phases are high-viscosity, solid-like gels, which can make large-scale dispersed cubic liquid crystalline phase particles difficult because of the problems associated with mixing and homogenizing. High-energy input is required, potentially degrading liquid crystalline structures. For example, high-energy input processes such as those employing high shear can physically degrade crystalline structures. High-energy input processes, such as those employing high temperatures, can chemically degrade the compounds making up the liquid crystalline structures. Furthermore, high energy input processes are costly and require more precise control and maintenance. Therefore, there is a need to provide methods for preparing cubic liquid crystalline phase materials that are less costly and more efficient than the methods involving bulk solid processing.
Dispersed Cubic Liquid Crystalline Gel Particles
Lamellar phases have a bilayer sheet structure. When a lamellar phase is dispersed in excess water, the lamellar phase may form vesicles and liposomes. “Vesicle” means an enclosed shell comprised of one bilayer of amphiphilic molecules. “Liposome” means an enclosed shell comprised of more than one bilayer of amphiphilic molecules. Vesicles and liposomes can be spheroidal, ellipsoidal, or irregularly shaped; however, spheroidal shells are the most stable.
Vesicles and liposomes suffer from the drawback that they are non-equilibrium states, which means that, inevitably, they will degrade. Furthermore, vesicles and liposomes are relatively expensive to manufacture and are more fragile than cubic liquid crystalline particles to shear-induced destruction. Therefore, there is a need to provide a stable, less expensive alternative to vesicles and liposomes.
Bulk cubic liquid crystalline gel can also be dispersed to form particles. Dispersed particles of cubic liquid crystalline phases are structurally distinct from vesicles and liposomes. Dispersed cubic gel particles have a cubic or spherical outer structure with a bicontinuous cubic internal structure. The bicontinuous cubic internal structure has distinct hydrophilic and lipophilic domains, and is described in S. Hyde et al., The Language of Shape, Elsevier, Amsterdam, 1997, pages 205–208, herein incorporated by reference.
Typically, cubic liquid crystalline gel particles are formed via fragmentation and dispersion of homogeneous bulk cubic liquid crystalline gel in excess solvent (i.e. water). Fragmentation is typically carried out in the liquid phase in combination with stabilizer/fragmentation agents such as polysaccharides, proteins, amphiphilic macromolecules and lipids, amphiphilic polymers, and amphiphilic compounds. Fragmentation also requires the use of a high-energy input process by, for example, high shear milling or sonication.
Fragmenting and dispersing solid and solid-like materials, such as bulk cubic liquid crystalline gel, is difficult and impractical above very small processing scales (e.g., on the order of several grams, or less) without significant energy input and hold time. This makes commercial scale production of dispersed cubic gels expensive and impractical. Furthermore, high energy input processes can create non-equilibrium structures, such as vesicles and liposomes. Therefore, there is a need to develop a means for producing dispersed cubic liquid crystalline gel particles that does not require a fragmentation step. There is still a further need to provide a method for forming cubic gel particles instantaneously by hydrating dry powder precursors with solvent. There is currently no way to form cubic liquid crystalline particles from a dry powder precursor, all current fragmentation and precursor processes utilize relatively large fractions of liquid.
It is a further object of this invention to provide an economical and practical method for producing easy-flowing dry powders that can be easily used to prepare commercial-scale quantities of colloidally stabilized cubic liquid crystalline gel particle dispersions upon contact with water.